Active film packaging based on bio-nanocomposite TiO2 and cinnamon essential oil for enhanced preservation of cheese quality.

This study involves the preparation of PLA/PBAT composite blend films incorporated with TiO2 and varying concentrations of cinnamon essential oil. The films were characterised for optical and mechanical properties, chemical composition, thermo-stability, surface hydrophobicity, inhibition of biofilm formation, anti-microbial efficiency against S. aureus and E. coli, and application on cheese. The thickness of the films increased with the increase in cinnamon oil concentration along with the water contact angle degree and highest UV-barrier properties with the PLA-PBAT-TiO2-7 %Cinn film. The best anti-bacterial activity was seen in the PLA-PBAT-TiO2-7 %Cinn film against S. aureus and E. coli. The cheese packed in PLA-PBAT-TiO2-7 %Cinn film has shown the least weight loss and enhanced antibacterial activity against E. coli for 12 days of storage. The use of cinnamon oil-loaded TiO2 incorporated in films showed positive effects on the shelf life, quality, and safety of a food product and has a high potential for use commercially.

Encapsulation of Essential Oils in Nanocarriers for Active Food Packaging.

Active packaging improves a packaging system's effectiveness by actively integrating additional components into the packaging material or the headspace around the packaging. Consumer demand and awareness have grown enough to replace chemical agents with natural active agents. Essential oils (EOs) are extensively distributed throughout nature but at low levels and sometimes with poor recovery yields, which poses an issue with their application in food. Due to the instability of EOs when added directly into a food product, they require encapsulation before being added to a packaging matrix such as liposomes, solid-lipid nanoparticles, nano-emulsions, cyclodextrins, and nanostructured lipid nano-carriers. This article is focused on the encapsulation of EOs in different types of nanocarriers. Nanocarriers can improve the efficiency of active substances by providing protection, stability, and controlled and targeted release. The advantages of the many types of nanocarriers that contain active substances that can be used to make antibacterial and antioxidant biopolymeric-based active packaging are discussed. A nanocarrier-encapsulated EO enables the controlled release of oil, stabilizing the packaging for a longer duration.

Comparing ultrafast excited state quenching of flavin 1,N6-ethenoadenine dinucleotide and flavin adenine dinucleotide by optical spectroscopy and DFT calculations.

Flavins are photoenzymatic cofactors often exploiting the absorption of light to energize photoinduced redox chemistry in a variety of contexts. Both flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) are used for this function. The study of these photoenzymes has been facilitated using flavin analogs. Most of these analogs involve modification of the flavin ring, and there is recent evidence that adenine (Ade)-modified FAD can affect enzyme turnover, but so far this has only been shown for enzymes where the adenine and flavin rings are close to each other in a stacked conformation. FAD is also stacked in aqueous solution, and its photodynamics are quite different from unstacked FAD or FMN. Oxidized photoexcited FAD decays rapidly, presumably through PET with Ade as donor and Fl* as acceptor. Definitive identification of the spectral signatures of Ade∙+ and Fl∙- radicals is elusive. Here we use the FAD analog Flavin 1,N6-Ethenoadenine Dinucleotide (εFAD) to study how different photochemical outcomes depend on the identity of the Ade moiety in stacked FAD and its analog εFAD. We have used UV-Vis transient absorption spectroscopy complemented by TD-DFT calculations to investigate the excited state evolution of the flavins. In FAD*, no radicals were observed, suggesting that FAD* does not undergo PET. εFAD* kinetics showed a broad absorption band that suggests a charge transfer state exists upon photoexcitation with evidence for radical pair formation. Surprisingly, significant triplet flavin was produced from εFAD* We hypothesize that the dipolar (ε)Ade moieties differentially modulate the singlet-triplet energy gap, resulting in different intersystem crossing rates. The additional electron density on the etheno group of εFAD supplies better orbital overlap with the flavin S1 state, accelerating charge transfer in that molecule.

Home-based pulmonary rehabilitation early after hospitalisation in COPD (early HomeBase): protocol for a randomised controlled trial.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterised by exacerbations of respiratory disease, frequently requiring hospital admission. Pulmonary rehabilitation can reduce the likelihood of future hospitalisation, but programme uptake is poor. This study aims to compare hospital readmission rates, clinical outcomes and costs between people with COPD who undertake a home-based programme of pulmonary rehabilitation commenced early (within 2 weeks) of hospital discharge with usual care. METHODS: A multisite randomised controlled trial, powered for superiority, will be conducted in Australia. Eligible patients admitted to one of the participating sites for an exacerbation of COPD will be invited to participate. Participants will be randomised 1:1. Intervention group participants will undertake an 8-week programme of home-based pulmonary rehabilitation commencing within 2 weeks of hospital discharge. Control group participants will receive usual care and a weekly phone call for attention control. Outcomes will be measured by a blinded assessor at baseline, after the intervention (week 9-10 posthospital discharge), and at 12 months follow-up. The primary outcome is hospital readmission at 12 months follow-up. ETHICS AND DISSEMINATION: Human Research Ethics approval for all sites provided by Alfred Health (Project 51216). Findings will be published in peer-reviewed journals, conferences and lay publications. TRIAL REGISTRATION NUMBER: ACTRN12619001122145.

The cyclin-like protein SPY1 overrides reprogramming induced senescence through EZH2 mediated H3K27me3.

Fully differentiated cells can be reprogrammed through ectopic expression of key transcription factors to create induced pluripotent stem cells. These cells share many characteristics of normal embryonic stem cells and have great promise in disease modeling and regenerative medicine. The process of remodeling has its limitations, including a very low efficiency due to the upregulation of many antiproliferative genes, including cyclin dependent kinase inhibitors CDKN1A and CDKN2A, which serve to protect the cell by inducing apoptotic and senescent programs. Our data reveals a unique cell cycle mechanism enabling mouse fibroblasts to repress cyclin dependent kinase inhibitors through the activation of the epigenetic regulator EZH2 by a cyclin-like protein SPY1. This data reveals that the SPY1 protein is required for reprogramming to a pluripotent state and is capable of increasing reprogramming efficiency.

Maternal and fetal incidental findings on antenatal magnetic resonance imaging.

BACKGROUND: Magnetic resonance imaging (MRI) examinations are increasingly used in antenatal clinical practice. Incidental findings are a recognized association with imaging and although in some circumstances their identification can alter management, they are often associated with increased anxiety, for both patient and clinician, as well as increased health care costs. OBJECTIVE: This study aimed to evaluate the incidence of unexpected findings in both the mother and fetus during antenatal MRI examinations. MATERIALS AND METHODS: A retrospective study was undertaken over a five-year period at St.. Thomas' Hospital in London. Maternal incidental findings were recorded from all clinical reports of all fetal MRIs performed (for clinical reasons and in healthy volunteers) during this period. Fetal incidental findings were recorded only in cases where women with uncomplicated pregnancies were participating as healthy volunteers. RESULTS: A total of 2,569 MRIs were included; 17% of women had maternal incidental findings. Of these, 1,099 were women with uncomplicated pregnancies who undertook research MRIs as healthy volunteers; fetal incidental findings were identified in 12.3%. CONCLUSION: Incidental findings are a common occurrence in antenatal MRI. Consideration should be given to counseling women appropriately before imaging and ensuring that robust local protocols are in place for follow-up and further management of such cases.

Patient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome.

Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multidisciplinary platform was established to functionally evaluate novel CHD gene candidates, based on whole-genome and iPSC RNA sequencing of a HLHS family-trio. Filtering for rare variants and altered expression in proband iPSCs prioritized 10 candidates. siRNA/RNAi-mediated knockdown in healthy human iPSC-derived cardiomyocytes (hiPSC-CM) and in developing Drosophila and zebrafish hearts revealed that LDL receptor-related protein LRP2 is required for cardiomyocyte proliferation and differentiation. Consistent with hypoplastic heart defects, compared to patents the proband's iPSC-CMs exhibited reduced proliferation. Interestingly, rare, predicted-damaging LRP2 variants were enriched in a HLHS cohort; however, understanding their contribution to HLHS requires further investigation. Collectively, we have established a multi-species high-throughput platform to rapidly evaluate candidate genes and their interactions during heart development, which are crucial first steps toward deciphering oligogenic underpinnings of CHDs, including hypoplastic left hearts.

Does Shorter Time to Treatment of Pediatric Femur Shaft Fractures Impact Clinical Outcomes?

BACKGROUND: Annual rankings by US News and World Report are a widely utilized metric by both health care leaders and patients. One longstanding measure is time to treatment of femur shaft fractures. Hospitals able to provide at least 80% of pediatric patients with an operating room start time within 18 hours of admission to the emergency department score better as part of the overall pediatric orthopaedic ranking. Therefore, it is important to determine whether the 18-hour treatment time for pediatric femur shaft fractures is a clinically meaningful metric. METHODS: A retrospective review of clinical outcomes of 174 pediatric patients (aged below 16 y) with isolated femur shaft fractures (Injury Severity Score=9) was conducted from 1997 to 2017 at a single level I pediatric trauma center. The 2 comparison groups were patients receiving fracture reduction within 18 hours of emergency department admission (N=87) or >18 hours (N=87). RESULTS: Patient, injury, and surgical characteristics were similar between the 2 groups. Both groups had a similar mean age (treatment <18 h=7.5 y; treatment >18 h=8.1 y). Patients who received treatment within 18 hours were more often immobilized postoperatively (70.1% vs. 53.5%; P=0.0362) and had a shorter median hospital length of stay (2 vs. 3 d; P=0.0047). There were no statistically significant differences in any outcomes including surgical site infection, time to weight-bearing (treatment <18 h mean=48.1 d vs. 52.5 d), time to complete radiographic fracture healing (treatment <18 h mean=258.9 d vs. 232.0 d), decreased range of motion, genu varus/valgus, limb length discrepancy, loss of reduction, or persistent pain. CONCLUSIONS: Treatment of pediatric femur shaft fractures within 18 hours does not impact clinical outcomes. National quality measures should therefore use evidence-based metrics to help improve the standard of care. LEVEL OF EVIDENCE: Therapeutic level III.

Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection.

Importance: Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death. Objective: To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility. Design, Setting, and Participants: This single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD registry from August 30, 2011, to August 2, 2018. Data analysis was performed from June 21, 2017, to December 30, 2019. Main Outcomes and Measures: Genetic loci and positional candidate genes associated with SCAD. Results: This study included 484 white women with SCAD (mean [SD] age, 46.6 [9.2] years) and 1477 white female controls in the discovery cohort (mean [SD] age, 64.0 [14.5] years) and 183 white women with SCAD (mean [SD] age, 47.1 [9.9] years) and 340 white female controls in the replication cohort (mean [SD] age, 51.0 [15.3] years). Associations with SCAD risk reached genome-wide significance at 3 loci (1q21.3 [OR, 1.78; 95% CI, 1.51-2.09; P = 2.63 × 10-12], 6p24.1 [OR, 1.77; 95% CI, 1.51-2.09; P = 7.09 × 10-12], and 12q13.3 [OR, 1.67; 95% CI, 1.42-1.97; P = 3.62 × 10-10]), and 7 loci had evidence suggestive of an association (1q24.2 [OR, 2.10; 95% CI, 1.58-2.79; P = 2.88 × 10-7], 3q22.3 [OR, 1.47; 95% CI, 1.26-1.71; P = 6.65 × 10-7], 4q34.3 [OR, 1.84; 95% CI, 1.44-2.35; P = 9.80 × 10-7], 8q24.3 [OR, 2.57; 95% CI, 1.76-3.75; P = 9.65 × 10-7], 15q21.1 [OR, 1.75; 95% CI, 1.40-2.18; P = 7.23 × 10-7], 16q24.1 [OR, 1.91; 95% CI, 1.49-2.44; P = 2.56 × 10-7], and 21q22.11 [OR, 2.11; 95% CI, 1.59-2.82; P = 3.12 × 10-7]) after adjusting for the top 5 principal components. Associations were validated for 5 of the 10 risk alleles in the replication cohort. In a meta-analysis of the discovery and replication cohorts, associations for the 5 SNVs were significant, with relatively large effect sizes (1q21.3 [OR, 1.77; 95% CI, 1.54-2.03; P = 3.26 × 10-16], 6p24.1 [OR, 1.71; 95% CI, 1.49-1.97; P = 4.59 × 10-14], 12q13.3 [OR, 1.69; 95% CI, 1.47-1.94; P = 1.42 × 10-13], 15q21.1 [OR, 1.79; 95% CI, 1.48-2.17; P = 2.12 × 10-9], and 21q22.11 [OR, 2.18; 95% CI, 1.70-2.81; P = 1.09 × 10-9]). Each index SNV was within or near a gene highly expressed in arterial tissue and previously linked to SCAD (PHACTR1) and/or other vascular disorders (LRP1, LINC00310, and FBN1). Conclusions and Relevance: This study revealed 5 replicated risk loci and positional candidate genes for SCAD, most of which are associated with extracoronary arteriopathies. Moreover, the alternate alleles of 3 SNVs have been previously associated with atherosclerotic coronary artery disease, further implicating allelic susceptibility to coronary artery atherosclerosis vs dissection.

Hypoglycemic thalamic activation in type 1 diabetes is associated with preserved symptoms despite reduced epinephrine.

Brain responses to low plasma glucose may be key to understanding the behaviors that prevent severe hypoglycemia in type 1 diabetes. This study investigated the impact of long duration, hypoglycemia aware type 1 diabetes on cerebral blood flow responses to hypoglycemia. Three-dimensional pseudo-continuous arterial spin labeling magnetic resonance imaging was performed in 15 individuals with type 1 diabetes and 15 non-diabetic controls during a two-step hyperinsulinemic glucose clamp. Symptom, hormone, global cerebral blood flow and regional cerebral blood flow responses to hypoglycemia were measured. Epinephrine release during hypoglycemia was attenuated in type 1 diabetes, but symptom score rose comparably in both groups. A rise in global cerebral blood flow did not differ between groups. Regional cerebral blood flow increased in the thalamus and fell in the hippocampus and temporal cortex in both groups. Type 1 diabetes demonstrated lesser anterior cingulate cortex activation; however, this difference did not survive correction for multiple comparisons. Thalamic cerebral blood flow change correlated with autonomic symptoms, and anterior cingulate cortex cerebral blood flow change correlated with epinephrine response across groups. The thalamus may thus be involved in symptom responses to hypoglycemia, independent of epinephrine action, while anterior cingulate cortex activation may be linked to counterregulation. Activation of these regions may have a role in hypoglycemia awareness and avoidance of problematic hypoglycemia.

Changing perceptions: a multicentre survey of final-year medical students' and junior doctors' perceptions of diabetes and endocrinology.

PURPOSE OF THE STUDY: The National Health Service is experiencing a recruitment crisis across many medical specialties. Diabetes and endocrinology (D&E) is failing to fill training posts with only 77%, 83% and 73% of posts filled overall in 2016, 2017 and 2018, respectively. STUDY DESIGN: We surveyed 316 final-year medical students and undifferentiated trainees (from foundation programme doctors to core medical trainees), across the South Thames, Northern and West Midlands deaneries in England to gain an understanding of perceptions of the specialty. RESULTS: 9% of respondents were considering a career in D&E. Factors such as 'being the medical registrar' (27%), being a 'non-procedural specialty' (23%) and 'looking after majority of general medical admissions' (22%) were cited as the most common reasons why D&E is an unattractive career choice. 51% reported inadequate exposure to D&E. Factors that made respondents more likely to want to pursue a career in D&E included having undertaken a placement in the specialty and having exposure to outpatient clinics. Methods to improve awareness and uptake, such as increased teaching and clinical exposure, and the opportunity to attend taster events were frequently highlighted. CONCLUSIONS: The results from this survey, the first of its kind on perceptions of D&E as a career pathway, reveal a worrying lack of interest in, and exposure to, D&E among current final-year medical students and undifferentiated trainees. These issues must be addressed in order to improve D&E recruitment rates.

Impaired Awareness of Hypoglycemia Disrupts Blood Flow to Brain Regions Involved in Arousal and Decision Making in Type 1 Diabetes.

OBJECTIVE: Impaired awareness of hypoglycemia (IAH) affects one-quarter of adults with type 1 diabetes and significantly increases the risk of severe hypoglycemia. Differences in regional brain responses to hypoglycemia may contribute to the susceptibility of this group to problematic hypoglycemia. This study investigated brain responses to hypoglycemia in hypoglycemia aware (HA) and IAH adults with type 1 diabetes, using three-dimensional pseudo-continuous arterial spin labeling (3D pCASL) functional MRI to measure changes in regional cerebral blood flow (CBF). RESEARCH DESIGN AND METHODS: Fifteen HA and 19 IAH individuals underwent 3D pCASL functional MRI during a two-step hyperinsulinemic glucose clamp. Symptom, hormone, global, and regional CBF responses to hypoglycemia (47 mg/dL [2.6 mmol/L]) were measured. RESULTS: In response to hypoglycemia, total symptom score did not change in those with IAH (P = 0.25) but rose in HA participants (P < 0.001). Epinephrine, cortisol, and growth hormone responses to hypoglycemia were lower in the IAH group (P < 0.05). Hypoglycemia induced a rise in global CBF (HA P = 0.01, IAH P = 0.04) but was not different between groups (P = 0.99). IAH participants showed reduced regional CBF responses within the thalamus (P = 0.002), right lateral orbitofrontal cortex (OFC) (P = 0.002), and right dorsolateral prefrontal cortex (P = 0.036) and a lesser decrease of CBF in the left hippocampus (P = 0.023) compared with the HA group. Thalamic and right lateral OFC differences survived Bonferroni correction. CONCLUSIONS: Responses to hypoglycemia of brain regions involved in arousal, decision making, and reward are altered in IAH. Changes in these pathways may disrupt IAH individuals' ability to recognize hypoglycemia, impairing their capacity to manage hypoglycemia effectively and benefit fully from conventional therapeutic pathways to restore awareness.

Rare Missense Variants in TLN1 Are Associated With Familial and Sporadic Spontaneous Coronary Artery Dissection.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an uncommon idiopathic disorder predominantly affecting young, otherwise healthy women. Rare familial cases reveal a genetic predisposition to disease. The aim of this study was to identify a novel susceptibility gene for SCAD. METHODS: Whole-exome sequencing was performed in a family comprised of 3 affected individuals and filtered to identify rare, predicted deleterious, segregating variants. Immunohistochemical staining was used to evaluate protein expression of the identified candidate gene. The prevalence and spectrum of rare (<0.1%) variants within binding domains was determined by next-generation sequencing or denaturing high-performance liquid chromatography in a sporadic SCAD cohort of 675 unrelated individuals. RESULTS: We identified a rare heterozygous missense variant within a highly conserved ß-integrin-binding domain of TLN1 segregating with familial SCAD. TLN1 encodes talin 1-a large cytoplasmic protein of the integrin adhesion complex that links the actin cytoskeleton and extracellular matrix. Consistent with high mRNA expression in arterial tissues, robust immunohistochemical staining of talin 1 was demonstrated in coronary arteries. Nine additional rare heterozygous missense variants in TLN1 were identified in 10 sporadic cases. Incomplete penetrance, suggesting genetic or environmental modifiers of this episodic disorder, was evident in the familial case and 5 individuals with sporadic SCAD from whom parental DNA was available. CONCLUSIONS: Our findings reveal TLN1 as a disease-associated gene in familial and sporadic SCAD and, together with abnormal vascular phenotypes reported in animal models of talin 1 disruption, implicate impaired structural integrity of the coronary artery cytoskeleton in SCAD susceptibility.

Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. OBJECTIVES: This study sought to test the association between the rs9349379 genotype and SCAD. METHODS: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. RESULTS: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. CONCLUSIONS: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

Long-Term Mortality Trends After Revision Total Knee Arthroplasty.

BACKGROUND: Long-term mortality following primary total knee arthroplasty (TKA) is lower than the general population. However, it is unknown whether this is true in the setting of revision TKA. We examined long-term mortality trends following revision TKA. METHODS: This retrospective study included 4907 patients who underwent 1 or more revision TKA between 1985 and 2015. Patients were grouped by surgical indications and followed until death or October 2017. The observed number of deaths was compared to the expected number of deaths using standardized mortality ratios (SMR) and Poisson regression models. RESULTS: Compared to the general population, patients who underwent revision TKA for infection (SMR, 1.45; 95% confidence interval [CI], 1.33-1.57; P < .0001) and fracture (SMR, 1.16; 95% CI, 1.00-1.34; P = .04) experienced a significantly higher mortality risk. Patients who underwent revision TKA for infection and fracture experienced excess mortality soon after surgery which became more pronounced over time. In contrast, the mortality risk among patients who underwent revision TKA for loosening and/or bearing wear was similar to the general population (SMR, 0.95; 95% CI, 0.89-1.02; P = .16). Aseptic loosening and/or wear and instability patients had improved mortality initially; however, there was a shift to excess mortality beyond 5 years among instability patients, and beyond 10 years among aseptic loosening and/or wear patients. CONCLUSION: Mortality is elevated soon after revision TKA for infection and fracture. Mortality is lower than the general population after revision TKA for loosening and/or bearing wear but gets worse than the general population beyond the first postoperative decade.

Risk of MGUS in relatives of multiple myeloma cases by clinical and tumor characteristics.

We and others have shown increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of patients with multiple myeloma (MM). Whether familial risk of MGUS differs by the MM proband's age at onset, tumor or clinical characteristics is unknown. MM and smoldering MM (SMM) cases (N = 430) were recruited from the Mayo Clinic in Rochester, Minnesota between 2005-2015. First-degree relatives over age 40 provided serum samples for evaluation of MGUS (N = 1179). Age and sex specific rates of MGUS among first-degree relatives were compared to a population-based sample. Cytogenetic subtypes were classified by Fluorescence in situ hybridization. MGUS was detected in 75 first-degree relatives for an age- and sex- adjusted prevalence of 5.8% (95% CI: 4.5-7.2). Prevalence of MGUS in first-degree relatives was 2.4 fold (95% CI: 1.9-2.9) greater than expected rates. Familial risk did not differ by proband's age at diagnosis, gender, isotype, IgH translocation, or trisomy. This study confirms first-degree relatives of MM cases have a significantly higher risk of MGUS compared to the general population, regardless of age, gender, or tumor characteristics. In selected situations, such as multiple affected first-degree relatives, screening of first-degree relatives of MM cases could be considered for follow-up and prevention strategies.

Prognostic and therapeutic significance of phosphorylated STAT3 and protein tyrosine phosphatase-6 in peripheral-T cell lymphoma.

Peripheral T cell lymphomas (PTCL) is a heterogenous group of non-Hodgkin lymphoma and many patients remain refractory to the frontline therapy. Identifying new prognostic markers and treatment is an unmet need in PTCL. We analyzed phospho-STAT3 (pSTAT3) expression in a cohort of 169 PTCL tumors and show overall 38% positivity with varied distribution among PTCL subtypes with 27% (16/59) in PTCL-NOS; 29% (11/38) in AITL, 57% (13/28) in ALK-negative ALCL, and 93% in ALK-pos ALCL (14/15), respectively. Correlative analysis indicated an adverse correlation between pSTAT3 and overall survival (OS). PTPN6, a tyrosine phosphatase and potential negative regulator of STAT3 activity, was suppressed in 62% of PTCL-NOS, 42% of AITL, 60% ALK-neg ALCL, and 86% of ALK-pos ALCL. Loss of PTPN6 combined with pSTAT3 positivity predicted an infwere considered significantferior OS in PTCL cases. In vitro treatment of TCL lines with azacytidine (aza), a DNA methyltransferase inhibitor (DNMTi), restored PTPN6 expression and decreased pSTAT3. Combining DNMTi with JAK3 inhibitor resulted in synergistic antitumor activity in SUDHL1 cell line. Overall, our results suggest that PTPN6 and activated STAT3 can be developed as prognostic markers, and the combination of DNMTi and JAK3 inhibitors as a novel treatment for patients with PTCL subtypes.

Improving Results of Surgery for Ebstein Anomaly: Where Are We After 235 Cone Repairs?

BACKGROUND: Ebstein anomaly has heterogeneous anatomy and numerous operative techniques are described. Cone repair provides a near anatomic tricuspid valve repair. The purpose of this study was to examine our experience with cone repair. METHODS: Cone repair was performed in 235 consecutive patients with Ebstein anomaly, 134 children (57%) and 101 adults (43%), from June 2007 to October 2015. Median age was 15.6 years (range, 6 months to 73 years). Cone repair was the first operation in 192 patients (82%), the second in 41 (17%), and the third in 2 (1%). Previous tricuspid valve repair had been performed in 27 (12%). Echocardiograms were obtained preoperatively and at hospital dismissal for all patients and for a subgroup of patients at least 6 months after cone repair (n = 81). RESULTS: Leaflet augmentation was done in 67 patients (28%), Sebening stitch in 57 (24.2%), neochordae in 49 (21%), and annuloplasty band in 158 (67%). Bidirectional cavopulmonary shunt was performed in 46 patients (20%). There was 1 early death (0.4%). Early reoperation was required in 14 patients (5.9%); re-repair was possible in 7 (50%). The majority of early reoperations (11 of 14; 79%) occurred in the first third of the series. Mean follow-up was 3.5 ± 2.5 years. There was sustained reduction in tricuspid regurgitation (p < 0.0001), a progressive decline in right ventricle size (p < 0.0001), and late increase in right ventricle fractional area change after initial decline (p < 0.0001). Freedom from late reoperation was 97.9% at 6 years. CONCLUSIONS: Cone repair is safe, and the learning curve is significant. Sustained reduction in tricuspid regurgitation and favorable changes in the right ventricle at follow-up suggest that cone repair has an advantageous impact on right ventricular remodeling.

Associations between elevated pre-treatment serum cytokines and peripheral blood cellular markers of immunosuppression in patients with lymphoma.

Higher ratios of the pre-treatment peripheral blood absolute lymphocyte (ALC) to absolute monocyte counts (AMC) are associated with improved outcomes in lymphoma. Conversely, elevated pre-treatment serum cytokines are associated with inferior outcomes. The relationship between pre-treatment serum cytokines and ALC/AMC ratios remains unknown. We studied twelve serum cytokines and the ALC/AMC ratios in 390 patients with untreated diffuse large B-cell, follicular, mantle cell, T-cell, and Hodgkin lymphoma. Different pre-treatment serum cytokine concentrations correlated with ALC, AMC, and ALC/AMC ratios depending on the lymphoma type. In the entire cohort (n = 390) lower ALC/AMC ratios modestly correlated with higher IL-2R (r = -0.36), IL-12 (r = -0.17), IP-10 (r = -0.23), and MIG (r = -0.32) concentrations (p < 0.001). Elevated IL-2R was independently associated with suppressed ALC (OR 2.69, 95% CI 1.77-4.07, p < 0.001), elevated AMC (OR 2.05, 95% CI 1.34-3.14, p < 0.001), and suppressed ALC/AMC ratios (OR 3.51, 95% CI 2.31-5.34, p < 0.001). Both elevated IL-2R (HR 2.27, 95% CI 1.48-3.49, p < 0.001) and suppressed ALC/AMC ratios (HR 1.53, 95% CI 1.03-2.28, p = 0.037) were independently associated with inferior overall survival. These data support the notion that elevated serum cytokines are immunosuppressive and provide further rationale to target the tumor microenvironment for therapeutic benefit.